Process for making 2-oxo-1-((substituted sulfonyl)amino)carbonzyl)azetidines and intermediates used therein

ABSTRACT

An improved process for making compounds having the formula ##STR1## includes subjecting an intermediate of the formula ##STR2## to hydrogenolysis in the presence of a ketonic solvent so as to simultaneously remove both Z-protecting groups from compound II while selectively reprotecting the --A 1  --NH 2  end of that molecule.

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparationof 2-oxo-1-[[(substituted sulfonyl)-amino]carbonyl]azetidines and,additionally, is directed to novel intermediates employed in such aprocess.

BACKGROUND OF THE INVENTION

Copending application Ser. No. 907,441, filed on September 15, 1986,describes 2-oxo-1-[[(substituted sulfonyl)-amino]carbonyl]azetidineshaving antibacterial activity. These azetidines can be characterized bythe general formula ##STR3## wherein A₁ represents various amino groupsand substituted N-heterocyclic groups. Preferred compounds, as disclosedby the application, are[[[[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]amino]-2-oxo-imidazolidinyl]sulfonyl]amino]carbonyl-2-oxo-azetidineshaving the formula ##STR4##

Several processes for preparing the above compounds are described. Inone process, protected β-lactams of the formula ##STR5## (wherein Protis an amino protecting group such as benzyloxycarbonyl,t-butoxycarbonyl, trityl and the like) are reacted with an isocyanate ofthe formula

    (iv)                                                       O═C═N--SO.sub.2 --Y,

wherein Y is a leaving group such as chlorine, to provide intermediatesof the formula ##STR6##

The Y leaving group can be displaced by reaction of a compound offormula (v) with the nucleophile of the formula ##STR7## for example, inthe case where A₁ of formula (i) is ##STR8## typically in the presenceof a base, to provide intermediates of the formula ##STR9## Deprotectionand acylation are described to couple the desired R₁ moiety at the3-amino site.

Alternatively, β-lactams other than compound (iii) are described assuitable for coupling with the isocyanate (iv) and acylation may becarried out at other points in the process.

To prepare the compound of formula (vi), a compound of the formula##STR10## is provided with hydroxyl group protection followed bycarboxyl activation and reacted with a compound of the formula ##STR11##

The so-formed compound (vi) is thereafter temporarily protected forcoupling with compound (v) and then must be reprotected for theacylation to add R₁.

In scaling up this process for the purpose of manufacturing thecompounds of formula (i), the numerous protection, deprotection andreprotection steps necessary in the described process render it costlyand less efficient than preferred. Additionally, it has been found thatbecause of the extremely water soluble nature of compound (ix) (andother H--A₁ --NH₂ intermediates), its isolation for use in the describedprocess is very difficult.

A more efficient process for making the compounds of formula (i) hasbeen sought.

SUMMARY OF THE INVENTION

In accordance with the present invention a novel process is disclosedwhich is useful for making antibacterial compounds having the formula##STR12## or pharmaceutically acceptable salts thereof wherein A₁ is##STR13##

R₁ is an acyl group derived from a carboxylic acid; and,

R₂ and R₃ are the same or different and each is hydrogen, alkyl,cycloalkyl, phenyl, substituted phenyl or a 4, 5, 6 or 7-memberedheterocycle (hereinafter referred to as R_(x)), or one of R₂ and R₃ ishydrogen and the other is halomethyl, dihalomethyl, trihalomethyl,alkoxycarbonyl, carboxyl, --CH₂ X₁ [wherein X₁ is amino (--NH₂),hydroxy, carboxyl, alkoxycarbonyl, alkanoylamino, phenylcarbonylamino,(substituted phenyl)carbonylamino, alkylsulfonyloxy, phenylsulfonyloxy,(substituted phenyl)sulfonyloxy, phenyl, substituted phenyl, cyano,##STR14## or --O--X₂ (wherein A₂, X₂, X₆ and X₇ are as hereinafterdefined)], or --O--X₂ [wherein X₂ is alkyl, substituted alkyl, phenyl,substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, alkanoyl,phenylalkanoyl, (substituted phenyl)alkanoyl, phenylcarbonyl,(substituted phenyl)carbonyl, or heteroarylcarbonyl], ##STR15## [whereinone of X₃ and X₄ is hydrogen and the other is hydrogen or alkyl, or X₃and X₄ when taken together with the carbon atom to which they areattached form a cycloalkyl group; and X₅ is formyl, alkanoyl,phenylcarbonyl, (substituted phenyl)carbonyl, phenylalkylcarbonyl,(substituted phenyl)alkylcarbonyl, carboxyl, alkoxycarbonyl,aminocarbonyl ##STR16## (substituted amino) carbonyl, or cyano(--C.tbd.N)], or ##STR17## [wherein A₂ is --(CH₂)_(m) --, --(CH₂)_(m)--O--, or --(CH₂)_(m) --NH, m is 0, 1 or 2, and X₆ and X₇ are the sameor different and each is hydrogen, alkyl, phenyl or substituted phenyl,or X₆ is hydrogen and X₇ is amino, substituted amino, alkanoylamino oralkoxy, or X₆ and X₇ when taken together with the nitrogen atom to whichthey are attached form a 4, 5, 6 or 7-membered heterocycle].

The present process, comprises treating a salt of the formula ##STR18##(wherein Z is benzyloxycarbonyl and X is selected from hydrogen, alkaliearth metals and tri- or tetra-alkylammonium (TA) groups) in thepresence of a ketonic solvent having the formula ##STR19## (wherein Rand R' are each alkyl or R and R' taken together with the carbon atom towhich they are attached are 5-, 6- or 7-membered cycloalkyl) withhydrogen in the presence of a catalyst, followed by acylation to providea compound having the formula ##STR20## Following removal of the##STR21## compound IV is reacted with a compound of the formula##STR22## wherein Prot is a protecting group, and the resulting productis deprotected to provide the compounds of formula I.

Also in accordance with the present invention, novel intermediates aredisclosed.

Detailed Description of the Invention

The β-lactams of formula I, and pharmaceutically acceptable saltsthereof, have activity against gram-positive and gram-negativeorganisms. These compounds can be used as agents to combat bacterialinfections (including urinary tract infections and respiratoryinfections) in mammalian species, such as domesticated animals (e.g.dogs, cats, cows, horses, and the like) and humans.

For combating bacterial infections in mammals, a compound of formula Ican be administered to a mammal in need thereof in an amount of about1.4 mg/kg/day to about 350 mg/kg/day, preferably about 14 mg/kg/day toabout 100 mg/kg/day. All modes of administration which have been used inthe past to deliver penicillins and cephalosporins to the site of theinfection are also contemplated for use with β-lactams of thisinvention. Such methods of administration include oral, intravenous,intramuscular, and as a suppository.

The compounds produced by the process of this invention form basic saltswith various inorganic and organic bases which are also within the scopeof this invention. Such salts include ammonium salts, alkali metalsalts, alkaline earth metal salts, salts with organic bases, e.g.dicyclohexylamine, benzathine, N-methyl-D-glucamine, hydrabamine and thelike. The pharmaceutically acceptable salts are preferred, althoughother salts are also useful, e.g. in isolating or purifying the product.

Some of the compounds produced by the process of this invention may becrystallized or recrystallized from solvents containing water. In thesecases, water of hydration may be formed. This invention contemplatesstoichiometric hydrates as well as compounds containing variable amountsof water that may be produced by processes such as lyophilization.

The β-lactams of formula I contain at least one chiral center--thecarbon atom in the 3-position of the β-lactam nucleus to which theacylamino substitutent ("R₁ --NH--") is attached. This invention isdirected to a process for producing those β-lactams which have beendescribed above, wherein the stereochemistry at the chiral center in the3-position of the β-lactam nucleus is the same as the configuration atthe carbon atom in the 6-position of naturally occurring penicillins(e.g. penicillin G) and as the configuration at the carbon atom in the7-position of naturally occurring cephamycins (e.g. cephamycin C). Alsoincluded within the scope of this invention are racemic mixtures whichcontain the above-described β-lactams.

Listed below are definitions of various terms used to describe theβ-lactams produced by the process of this invention. These definitionsapply to the terms as they are used throughout the specification (unlessthey are otherwise limited in specific instances) either individually oras part of a larger group.

The terms "alkyl" and "alkoxy" refer to both straight and branched chaingroups. Those groups having 1 to 10 carbon atoms are preferred.

The terms "cycloalkyl" and "cycloalkenyl" refer to cycloalkyl andcycloalkenyl groups having 3, 4, 5, 6 or 7 carbon atoms.

The term "substituted alkyl" refers to alkyl groups substituted with oneor more (preferably 1, 2 or 3) azido, amino (--NH₂), halogen, hydroxy,carboxy, cyano, alkoxycarbonyl, aminocarbonyl, alkanoyloxy, alkoxy,phenyloxy, (substituted phenyl)oxy, alkylsulfinyl, or alkylsulfonylgroups.

The terms "alkanoyl", "alkenyl", and "alkynyl" refer to both straightand branched chain groups. Those groups having 2 to 10 carbon atoms arepreferred.

The terms "halogen" and "halo" refer to fluorine, chlorine, bromine andiodine.

The term "substituted phenyl" refers to a phenyl group substituted with1, 2 or 3 amino (--NH₂), halogen, hydroxyl, trifluoromethyl, alkyl (of 1to 4 carbon atoms), alkoxy (of 1 to 4 carbon atoms), alkanoyloxy,aminocarbonyl, or carboxy groups.

The expression "a 4, 5, 6 or 7-membered heterocycle" (referred to as"R_(x) ") refers to substituted and unsubstituted, aromatic andnon-aromatic groups containing one or more (preferably 1, 2 or 3)nitrogen or oxygen atoms. Exemplary substituents are oxo (═O), halogen,hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbons,alkoxy of 1 to 4 carbons, alkylsulfonyl, phenyl, substituted phenyl2-furfurylideneamino ##STR23## benzylideneamino and substituted alkylgroups (wherein the alkyl group has 1 to 4 carbons). One type of "4, 5,6 or 7-membered heterocycle" is the "heteroaryl" group. The term"heteroaryl" refers to those 4, 5, 6 or 7-membered heterocycles whichare aromatic. Exemplary heteroaryl groups are substituted andunsubstituted pyridinyl, furanyl, pyrrolyl, 1,2,3-triazolyl,1,2,4-triazolyl, imidazolyl, pyrimidinyl, oxazolyl, triazinyl, andtetrazolyl. Exemplary nonaromatic heterocycles (i.e. fully or partiallysaturated heterocyclic groups) are substituted and unsubstitutedazetidinyl, oxetanyl, piperidinyl, piperazinyl, imidazolidinyl,oxazolidinyl, pyrrolidinyl, tetrahydropyrimidinyl and hexahydroazepinyl.Exemplary of the substituted 4, 5, 6 or 7-membered heterocycles are1-alkyl-3-azetidinyl, 2-oxo-1-imidazolidinyl,3-alkylsulfonyl-2-oxo-1-imidazolidinyl, 3benzylideneamino-2-oxo-1-imidazolidinyl, 3-alkyl-2-oxo-1-imidazolidinyl,3-phenyl (or substituted phenyl)-2-oxo-1-imidazolidinyl,3-benzyl-2-oxo-1-imidazolidinyl,3-(2-aminoethyl)-2-oxo-1-imidazolidinyl, 3-amino-2-oxo-1-imidazolidinyl,3-[(alkoxycarbonyl)amino]-2-oxo-1-imidazolidinyl, 3-[2-[(alkoxycarbonyl)amino]ethyl]-2-oxo-1-imidazolidinyl,2-oxo-1-pyrrolidinyl, 2-oxo-3-oxazolidinyl,4-hydroxy-6-methyl-2-pyrimidinyl, 2-oxo-1-hexahydroazepinyl,2-oxo-3-pyrrolidinyl, 2-oxo-3-tetrahydrofuranyl,2,3-dioxo-1-piperazinyl, 2,5-dioxo-1-piperazinyl,4-alkyl-2,3-dioxo-1-piperazinyl, and 4-phenyl-2,3-dioxo-1-piperazinyl.

The term "substituted amino" refers to a group having the formula --NX₈X₉ wherein X₈ is hydrogen, alkyl, phenyl, substituted phenyl,phenylalkyl or (substituted phenyl)alkyl, and X₉ is alkyl, phenyl,substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, hydroxy,cyano, alkoxy, phenylalkoxy, or amino (--NH₂).

The term "acyl" refers to all organic radicals derived from an organicacid (i.e. a carboxylic acid) by removal of the hydroxyl group. Certainacyl groups are, of course, preferred but this preference should not beviewed as a limitation of the scope of this invention. Exemplary acylgroups are those acyl groups which have been used in the past to acylateβ-lactam antibiotics including 6-aminopenicillanic acid and derivativesand 7-aminocephalosporanic acid and derivatives; see for example,Cephalosporins and Penicillins, edited by Flynn, Academic Press (1972),German Offenlegungsschrift 2,716,677, published Oct. 10, 1978, BelgianPat. No. 867,994, published Dec. 11, 1978, U.S. Pat. No. 4,152,432,issued May 1, 1979, U.S. Pat. No. 3,971,778, issued July 27, 1976, U.S.Pat. No. 4,172,199, issued Oct. 23, 1979, and British Pat. No.1,348,894, published Mar. 27, 1974. The portions of these referencesdescribing various acyl groups are incorporated herein by reference. Thefollowing list of acyl groups is presented to further exemplify the term"acyl"; it should not be regarded as limiting that term. Exemplary acylgroups are:

(a) Aliphatic groups having the formula ##STR24## wherein R_(a) isalkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, cyclohexadienyl, oralkyl or alkenyl substituted with one or more halogen, cyano, nitro,amino, mercapto, alkylthio, or cyanomethylthio groups;

(b) Carbocyclic aromatic groups having the formula ##STR25## wherein nis 0, 1, 2 or 3; R_(b), R_(c) and R_(d) each is independently hydrogen,halogen, hydroxyl, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4carbon atoms, alkoxy of 1 to 4 carbon atoms or aminomethyl; and R_(e) isamino, hydroxyl, a carboxyl salt, protected carboxyl, formyloxy, a sulfosalt, a sulfoamino salt, azido, halogen, hydrazino, alkylhydrazino,phenylhydrazino, or [(alkylthio)thioxomethyl]thio;

Preferred carbocyclic aromatic acyl groups include those having theformula ##STR26## (R_(e) is preferably a carboxyl salt or sulfo salt)and ##STR27## (R_(e) is preferably a carboxyl salt or sulfo salt); (c)Heteroaromatic groups having the formula ##STR28## wherein n is 0, 1, 2or 3; R_(e) is as defined above; and R_(f) is a substituted orunsubstituted 5-, 6- or 7-membered heterocyclic ring containing 1, 2, 3or 4 (preferably 1 or 2) nitrogen, oxygen and sulfur atoms. Exemplaryheterocyclic rings are thienyl, furyl, pyrrolyl, pyridinyl, pyrazolyl,pyrazinyl, thiazolyl, pyrimidinyl, thiadiazolyl and tetrazolyl.Exemplary substitutents are halogen, hydroxyl, nitro, amino, protectedamino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1to 4 carbon atoms, or ##STR29##

Preferred heteroaromatic acyl groups include those groups of the aboveformulas wherein R_(f) is 2-amino-4-thiazolyl,2-amino-5-halo-4-thiazolyl, 4-aminopyrimidin-2-yl,5-amino-1,2,4-thiadiazol-3-yl, 2-thienyl, 2-furanyl, or6-aminopyridin-2-yl;

(d) [[(4-Substituted-2,3-dioxo-1-piperazinyl)carbonyl]amino]arylacetylgroups having the formula ##STR30## wherein R_(g) is an aromatic group(including carbocyclic aromatics such as those of the formula ##STR31##and heteroaromatics as included within the definition of R_(f)); andR_(h) is alkyl, substituted alkyl (wherein the alkyl group issubstituted with one or more halogen, cyano, nitro, amino or mercaptogroups), arylmethyleneamino (i.e. --N═CH--R_(g) wherein R_(g) is asdefined above), arylcarbonylamino (i.e. ##STR32## wherein R_(g) is asdefined above) or alkylcarbonylamino;

Preferred[[(4-substituted-2,3-dioxo-1-piperazinyl)carbonyl]amino]arylacetylgroups include those wherein R_(h) is ethyl, phenylmethyleneamino or2-furylmethyleneamino;

(e) (Substituted oximino)arylacetyl groups having the formula ##STR33##wherein R_(g) is as defined above and R_(i) is hydrogen, alkyl,cycloalkyl, ##STR34## 2-pyrrazolylmethyl, (2-oxo-3-pyrrolidinyl)methyl,alkylaminocarbonyl, arylaminocarbonyl (i.e. ##STR35## wherein R_(g) isas defined above) or substituted alkyl (wherein the alkyl group issubstituted with one or more halogen, cyano, nitro, amino, mercapto,alkylthio, aromatic group (as defined by R_(g)), carboxyl (includingsalts thereof), amido, alkoxycarbonyl, phenylmethoxycarbonyl,diphenylmethoxycarbonyl, hydroxyalkoxyphosphinyl, dihydroxyphosphinyl,hydroxy(phenylmethoxy)phosphinyl, dialkoxyphosphinyl or tetrazolylsubstituents;

Preferred (substituted oxyimino)arylacetyl groups include those whereinR_(g) is 2-amino-4-thiazolyl. Also preferred are those groups whereinR_(i) is methyl, ethyl, carboxymethyl, 1-carboxy-1-methylethyl,2,2,2-trifluoroethyl or 1-carboxycyclopropyl;

(f) (Acylamino)arylacetyl groups having the formula ##STR36## whereinR_(g) is as defined above and R_(j) is ##STR37## amino, alkylamino,(cyanoalkyl)amino, amido, alkylamido, (cyanoalkyl)amido, ##STR38##

Preferred (acylamino)arylacetyl groups of the above formula includethose groups wherein R_(j) is amino or amido. Also preferred are thosegroups wherein R_(g) is phenyl or 2-thienyl;

(g) [[[3-Substituted-2-oxo-1-imidazolidinyl]carbonyl]amino]arylacetylgroups having the formula ##STR39## wherein R_(g) is as defined aboveand R_(k) is hydrogen, alkylsulfonyl, arylmethyleneamino (i.e.--N═CH--R_(g) wherein R_(g) is as defined above), ##STR40## (whereinR_(m) is hydrogen, alkyl or halogen substituted alkyl), aromatic group(as defined by R_(g) above), alkyl or substituted alkyl (wherein thealkyl group is substituted with one or more halogen, cyano, nitro, aminoor mercapto groups);

Preferred[[3-substituted-2-oxo-1-imidazolidinyl]carbonyl]amino]arylacetyl groupsof the above formula include those wherein R_(g) is phenyl or 2-thienyl.Also preferred are those groups wherein R_(k) is hydrogen,methylsulfonyl, phenylmethyleneamino or 2-furylmethyleneamino.

The process for preparing the compounds of formula I, described incopending application Ser. No. 907,441 filed Sept. 15, 1986, has beenimproved.

In accordance with the present invention, the β-lactams of formula I canbe prepared by first reacting a 3-protected amino-2-azetidinone havingthe formula ##STR41##

wherein Z is benzyloxycarbonyl, with an isocyanate having the formula

    VII                                                        O═C═N--SO.sub.2 --Y,

wherein Y is a leaving group, such as chlorine, in the presence of aninert organic solvent, e.g. ethyl acetate, tetrahydrofuran,dimethoxyethane, dichloromethane, acetonitrile or mixtures thereof, asdisclosed in copending application Ser. No. 907,441, filed Sept. 15,1986.

Reaction, thereafter, with an intermediate of the formula

    VIII                                                       H--A.sub.1 --NH--Z,

in the presence of a tertiary alkylamine, e.g. triethylamine ordiisopropylethylamine, and a solvent, such as dichloromethane, providesthe novel intermediate of the formula ##STR42## that is, the compoundsof formula II wherein X is M and wherein M is hydrogen or an alkaliearth metal, e.g. calcium or sodium.

Preferably, compound IX is treated with a tri- or tetra-alkylammonium(TA) sulfate, e.g. tetrabutylammonium sulfate, to provide the TA salt ofthe formula ##STR43## that is, the compounds of formula II wherein X isTA.

The novel bis-Z protected intermediates of formula II below ##STR44##are considered part of the present invention.

A salt of formula II, i.e. the M salt of formula IX or preferably the TAsalt of formula X, in a solvent, e.g. methylene chloride, and in thepresence of a ketonic solvent of the formula ##STR45## is reduced, forexample, with hydrogen in the presence of a catalyst such as palladiumon carbon. The preferred ketonic solvents of formula III includeacetone, diethyl ketone and methyl ethyl ketone. This is followedimmediately by acylation of the salt and treatment with trifluoroaceticacid in methanol to provide ##STR46##

A key to the process described above is that the salt of formula II isdeprotected at both the 3-amino- and the imidazolidinyl amino sites andimmediately thereafter is selectively reprotected at the imidazolidinylamino site with the alkylidine group, ##STR47## before the acylation byreaction with the ketonic solvent. Without this selective in situreprotection, acylation would be expected to occur at both ends of themolecule.

Well known acylation techniques can be used to convert an intermediateof formula II (that is, intermediates IX or X) to a correspondingintermediate of formula XI. Exemplary techniques include reaction of acompound of formula II, treated as described above, with a carboxylicacid (R₁ --OH), or corresponding carboxylic acid halide or carboxylicacid anhydride. The reaction should preferably take place in thepresence of diisopropylethylamine. Optionally, the reaction with acarboxylic acid will proceed in the presence of a carbodiimide such asdicyclohexylcarbodiimide and a substance capable of forming an activeester in situ such as N-hydroxybenzotriazole. In those instances wherethe acyl group (R₁) contains reactive functionality (such as amino orcarboxyl groups) it may be necessary to first protect those functionalgroups, then carry out the acylation reaction, and finally deprotect theresulting product.

Preferably, compound XI can be treated with an alkoxyamine, orO-benzylhydroxylamine, in the presence of a tertiary amine, e.g.diisopropylethylamine, and pyridinium p-toluene sulfonate in an organicsolvent, e.g. methylene chloride or acetonitrile, to remove ##STR48##This is immediately followed by reaction with an intermediate of theformula ##STR49## wherein Prot is a protecting group other than benzyl,such as t-butoxycarbonyl or typical phenol protecting groups, e.g.acetates, benzoates and pivalates, to provide a compound of the formula##STR50##

Alternatively, compound XI can be treated with a mild aqueous acid, suchas sodium hydrogen phosphate, in the presence of an organic solvent,such as acetonitrile, to provide a compound of the formula ##STR51##

Compound XIV can thereafter be reacted with compound XII above toprovide the compounds of formula XIII.

Compound XIII is thereafter deprotected to form the compounds of formulaI, or salts thereof, by techniques known in the art, such as bytreatment with trifluoroacetic acid.

The intermediates of formula XII can be prepared by treating a compoundof the formula ##STR52## with benzyl alcohol in the presence of asolvent, e.g. cyclohexane, and a strong acid, e.g. p-toluenesulfonicacid, to provide ##STR53##

Compound XVI in a solvent, e.g. methylene chloride, can be reacted with

    XVII                                                       (Prot).sub.2.O

or with a compound having the formula ##STR54## (wherein A₃ is alkyl,cycloalkyl or phenyl) in the presence of an acetylation catalyst, suchas dimethylaminopyridine, to provide the compound ##STR55##

Reduction of compound XIX, such as by treating with hydrogen in thepresence of a catalyst, such as palladium on carbon, in a solvent, suchas methylene chloride, provides a compound of the formula ##STR56##

Preferably, "Prot" is t-butoxy carbonyl (BOC) to provide a preferred andnovel intermediate ##STR57##

Although the typical phenol protecting groups, i.e. acetates, benzoatesand pivalates, are suitable for use on compound XX in the presentprocess, it has been found that the deprotection process can cause somecleavage of the β-lactam ring resulting in lower yields. By using thebis-BOC protected acid of formula XXa, a higher yield is realized. Thiswas unexpected since BOC is typically an amine protecting group.

Compound XX, in a solvent such as dichloromethane or acetonitrile in thepresence of dimethylformamide as a catalyst, is thereafter treated witha chlorinating agent, e.g. oxalyl chloride, and pyridine to provide theintermediate of formula XII.

To make the intermediates of formula VIII, a compound of the formula

    XXI                                                        H--A.sub.1 --H

is treated with a nitrosating reagent, e.g. sodium nitrite in aqueoussulfuric acid, followed by reduction, e.g. by treatment with zinc, andthereafter reacted with a compound of the formula

    XXII                                                       halogen--Z

followed by treatment with an acid, e.g. hydrochloric.

The present process is particularly suitable for preparation of thepreferred compounds of formula I wherein A₁ is ##STR58## that is,##STR59## in which case compound VIII in the above reactions isrepresented by ##STR60##

The preparation of the unprotected form of compound XXIV has beendescribed (Michels and Gever, J. Amer. Chem. Soc., 1956, 78, 5349), andthis unprotected form was used in copending application Ser. No.907,441. However, due to the extreme water solubility of the unprotectedform, its isolation is extremely difficult. The protected intermediateXXIV used in the present process is prepared by treating a compound ofthe formula ##STR61## in suspension with sulfuric acid with sodiumnitrite and then with zinc dust. Thereafter, the pH may be adjusted tobetween about 8.0 and 9.0, e.g. with sodium hydroxide, and theso-treated compound is reacted with a compound of formula XXII and thentreated with an acid, e.g. hydrochloric, to provide the intermediate offormula XXIV. The benzyloxycarbonyl-protected compound of formula XXIVis much less soluble in water than the unprotected form and thereforeits isolation is substantially easier.

The process of the present invention is particularly useful forpreparation of the product of formula I wherein R₁ is ##STR62## or thedisodium salt thereof, and wherein R₂ and R₃ are each hydrogen, that is,the compound having the formula ##STR63##

The present invention will now be described by reference to thefollowing examples, however, it is not meant to be limited to thedetails therein.

EXAMPLE 12-[[[1-(2-Amino-4-thiazolyl)-2-[[1-[[[[3-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy-2-methylpropanoicacid, disodium salt A. (2-Oxo-1-imidazolidinyl)carbamic acid,phenylmethyl ester

To a suspension of imidazolidinone (252 g, 2.98 mole) and 2N hydrogensulfate (4 l) at 0° C. was added sodium nitrite (101 g, 1.46 mole)portionwise over 15 minutes while maintaining a reaction temperature of1° C. After the addition was complete the suspension was stirred 2.5hours at 0° C.

The 0° C. mixture was then treated with zinc dust (220 g, 3.36 mole) insmall portions over 1 hour not letting the reaction temperature exceed5° C. The resulting mixture was stirred at 0° C. for 30 minutes, thecold bath was removed and the reaction stirred 3 hours longer at roomtemperature. The mixture was filtered through a pad of Celite to removeexcess zinc, and the Celite was washed with water (500 ml).

The colorless filtrate was taken to pH 8.50 with the addition of 25%aqueous sodium hydroxide forming a thick colorless suspension. Benzylchloroformate (208 g, 1.45 mole) was added and the pH was maintained at8.50-9.0 with the addition of the sodium hydroxide solution. After 1hour an additional portion of benzyl chloroformate (20 ml, 0.14 mole)was added and the pH was maintained at 8.50 with the addition of thesodium hydroxide solution. After stirring for an additional 2 hours, thereaction mixture was adjusted to pH 2.0 by the addition of aqueoushydrochloric acid (concentrated hydrochloric acid:water, 1:1). Thereaction mixture was cooled to 18° C. and then filtered to obtain acolorless solid. This material was washed with water (2.5 l) then withether (800 ml), and air dried to give 283 g of the crude title Acompound. Recrystallization from acetonitrile (900 ml) followed byrecrystallization from methanol (550 ml) gave 220 g of the final title Acompound.

B.(S)-[2-Oxo-1-[[[[2-oxo-3-[[(phenylmethoxy)carbonyl]amino]-1-imidazolidinyl]sulfonyl]amino]carbonyl]-3-azetidinyl]carbamicacid, phenylmethyl ester, monosodium salt

To a stirred suspension of (S)-(2-oxo-3-azetidinyl)carbamic acid,phenylmethyl ester (2 g, 9.08 mmol) in ethyl acetate (60 mL) at -30° C.under argon was added chlorosulfonyl isocyanate (0.80 mL, 9.19 mmol).The resulting mixture was stirred at -30° C. and the suspensiongradually clears to give a colorless solution. After 1 hour at -30° C.,dichloromethane (30 mL) was added followed by compound A (2.24 g, 9.52mmol). To the resulting suspension at -30° C. was added dropwise over 15minutes a solution of diisopropylethylamine (3.16 mL, 18.14 mmol) indichloromethane (30 mL). Dichloromethane (6 mL) was used to rinse theaddition funnel. The reaction was then allowed to warm to roomtemperature. After stirring overnight, the reaction mixture (paleyellow) was washed with dilute hydrogen sulfate (30 mL) and water. Afterdrying over anhydrous magnesium sulfate, the solvent was removed atreduced pressure to give a pale yellow oil. This material was dissolvedin acetone (40 mL) and water (20 mL). The resulting solution (pH˜2-3)was adjusted to pH 6.5 by the addition of 1N sodium hydroxide. Theresulting solution was seeded and the acetone was slowly removed atreduced pressure. The resulting slurry was filtered and the solid waswashed with water, absolute ethanol, and with ether (to aid in drying).After drying under vacuum over phosphorus pentoxide, 4.41 g of the titleB compound was obtained as a colorless solid, m.p. 220° C.

C.(S)-[2-Oxo-1[[[[2-oxo-3-[[(phenylmethoxy)carbonyl]amino]-1-imidazolidinyl]sulfonyl]amino]carbonyl]-3-azetidinyl]carbamicacid, phenylmethyl ester 1.0 tetrabutylammonium salt

A solution of tetrabutylammonium hydrogen sulfate (6 g, 17.67 mmol) inwater (60 mL) was adjusted to a pH of 3.5 by the addition of 1N sodiumhydroxide. This solution was then added to dichloromethane (300 mL)followed by the addition of the title B compound (10 g, 17.17 mmol).After stirring vigorously for 30 minutes, the dichloromethane layer wasseparated and washed with water. After drying over anhydrous magnesiumsulfate, the solvent was removed at reduced pressure to afford a foamwhich when crushed affords 13.49 g of the title C compound as a densesolid, m.p. 75.7°-116.3° C.

Analysis calc'd for C₃₉ H₅₉ N₇ O₉ S.0.03CH₂ Cl₂ : C, 58.27; H, 7.40; N,12.19; S, 3.99; Cl 0.26;

Found: C, 57.94; H, 7.33; N, 12.15; S, 4.05; Cl, 0.20.

D.(S)-2-[[[1-(2-Amino-4-thiazolyl)-2-[[1-[[[[3-[(1-methylethylidene)amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoicacid, diphenylmethyl ester

A mixture of the title C compound (10 g, 12.47 mmol) and 10% palladiumon carbon (1 g) in dichloromethane (80 mL), acetone (40 mL), and water(0.5 mL) was stirred under a hydrogen atmosphere with a continuous flowof hydrogen through the reaction vessel. Additional solvent was addedduring the reaction to replace that lost by the hydrogen purge. After 3hours, chromatography analysis showed the reaction to be complete andthe reaction vessel was purged with argon. To the resulting mixture wasadded(Z)-2-amino-α-[[2-(diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy]imino]-4-thiazoleaceticacid, 1H-benzotriazol-1-yl ester (6.94 g, 12.47 mmol) followed bydiisopropylethylamine (2.17 mL, 12.47 mmol). After stirring at roomtemperature under argon for 15 hours, the catalyst was removed byfiltration through Celite and the Celite bed was washed withdichloromethane. The filtrate was concentrated at reduced pressure andthe residue was dissolved in dichloromethane (˜600 mL). The resultingsolution was washed with pH 4.0 phosphate buffer and pH 7.0 phosphatebuffer. After drying over anhydrous magnesium sulfate, the solvent wasremoved at reduced pressure. The resulting viscous yellow oil was thenplaced under vacuum for ˜3 hours to give a yellow foam. This foam wasdissolved in methanol (65 mL). To the resulting solution was addedtrifluoroacetic acid (1 mL, 12.98 mmol, 1.04 eq) dropwise over ˜1minute. After ˜2 minutes, the solution became cloudy and a precipitatebegan to form. After stirring for 1 hour at room temperature, themixture was cooled to 0° C. After stirring for 1 hour at 0° C., theproduct was collected by filtration and washed twice with ice coldmethanol (15 mL). The material was then dried under vacuum overphosphorus pentoxide to afford 8.33 g of the title D compound as anoff-white granular solid, m.p. 165° C.

Analysis calc'd for C₃₂ H₃₅ N₉ O₉ S₂.1.2 m H₂ O: C, 49.57; H, 4.86; N,16.26; S, 8.27; F, 0.00; KF, 2.8;

Found: C, 49.54; H, 4.58; N, 15.92; S, 8.47; F, 0.00; KF, 2.8.

E. 1,4-Dihydro-5-hydroxy-4-oxo-2-pyridinecarboxylic acid, phenylmethylester

A vessel equipped with a water separator was charged with1,4-dihydro-5-hydroxy-4-oxo-2-pyridine carboxylic acid monohydrochloride(100 g, 0.52 mole), p-toluenesulfonic acid (123.5 g, 0.65 mole), benzylalcohol (1000 ml) and cyclohexane (625 ml). The resulting mixture wasrefluxed for 24 hours during which 68 ml of water was collected. Theheterogeneous mixture was cooled (˜50° C.) and cyclohexane (725 ml) wasadded. After stirring for 1 hour at ambient temperature, the solid wasfiltered, washed with 20% cyclohexane in ethyl acetate (1000 ml) anddried to give 207 g of a white solid. This material was suspended in icecold water (1200 ml) and the pH was adjusted to 8.0 with the addition of15% sodium hydroxide solution (˜150 ml). After stirring for 1 hour thematerial was collected by filtration, washed with water (1000 ml), anddried to give 107.1 g of the title E compound as a colorless solid, m.p.115° C. (dec).

Analysis calc'd for C₁₃ H₁₁ NO₄.0.11M H₂ O: C, 63.16; H, 4.57; N, 5.67;KF, 0.80;

Found: C, 63.37; H, 4.60; N, 5.69; KF, 0.77.

F. 4,5-Bis[[(1,1-dimethylethoxy)carbonyl]oxy]-2-pyridinecarboxylic acid,phenylmethyl ester

To a suspension of crude title E compound (1.40 g, 5.71 mmol) in drydichloromethane (30 mL) at room temperature under argon was added4-dimethylaminopyridine (100 mg, 0.82 mmol, 0.14 eq) followed bydi-tert-butyl dicarbonate (2.74 g, 2.2 eq). Vigorous gas evolution beganalmost immediately. After stirring for 15 minutes, an additional portionof di-tert-butyl dicarbonate (200 mg, 0.92 mmol, 0.16 eq) was added.After stirring for an additional 15 minutes, the reaction mixture wasdiluted with ether and washed twice with 0.2M phosphate buffer, 1Nsodium hydrogen carbonate, and brine. After drying over anhydrousmagnesium sulfate, the solvent was removed at reduced pressure to give abright yellow oil. This material was combined with that obtained fromanother reaction (1 g) and chromatographed to afford 3.83 g of the titleF compound as a viscous colorless oil.

Analysis calc'd for C₂₃ H₂₇ NO₈.0.25 m H₂ O: C, 61.39; H, 6.16; N, 3.11;KF, 1.00;

Found: C, 61.53; H, 6.19; N, 3.04; KF, 1.00.

G. 4,5-Bis[[(1,1-Dimethylethoxy)carbonyl]oxy]-2-pyridinecarboxylic acid

A mixture of the title F compound (˜3.50 g, 6.85 mmol) and 10% palladiumon carbon (300 mg) in dichloromethane (60 mL) was stirred under ahydrogen atmosphere. Chromatography analysis after 75 minutes shows thereaction to be essentially complete. The catalyst was removed byfiltration through Celite over a Teflon millipore membrane (0.50μ) andfilter bed washed with dichloromethane. The filtrate was concentrated atreduced pressure and the residue was chased twice with ether (10 mL).The residue was dissolved in ether (˜7 mL) and seeded. After standingfor ˜15 minutes, the solvent was removed to afford 2.30 g of the title Gcompound as a colorless solid, m.p. 107° C.

Analysis calc'd for C₁₆ H₂₁ NO₈ : C, 54.08; H, 5.96; N, 3.94;

Found: C, 54.31; H, 6.01; N, 3.87.

H. 4,5-Bis[[(1,1-Dimethylethoxy)carbonyl]oxy]-2-pyridinecarboxylic acidchloride

A solution of the title G compound (1.920 g, 5.403 mmol) in drydichloromethane (58 mL) under argon was cooled to 0° C. and to it wasadded N,N-dimethylformamide (0.0123 mL, 0.159 mmol) and pyridine (0.437mL, 5.403 mmol). To the solution was added dropwise over 10 minutesdistilled oxalyl chloride (0.486 mL, 5.571 mmol). Gas evolved rapidlyduring the addition. For 1 hour after addition was complete, a sweep ofargon was maintained while the mixture was rapidly stirred to facilitateremoval of residual gases. The resulting very pale blue solution wascooled further to -40° C. and maintained there.

I.[3S(Z)]-2-[[[1-(2-Amino-4-thiazolyl)-2-[[1-[[[[3-[[[4,5-bis[[(1,1-dimethylethoxy)carbonyl]oxy]-2-pyridinyl]carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoicacid, diphenylmethyl ester

The title D compound (4.00 g, 5.307 mmol) was slurried in drydichloromethane (76 ml) under argon. Addition of diisopropylethylamine(0.924 ml, 5.305 mmol) caused dissolution in 15 minutes. The nearlycolorless solution was cooled to -20° C. and to it was added solidpyridinium p-toluenesulfonate (0.266 g, 1.06 mmol) which dissolved in 5minutes. To the cold solution was then added dropwiseO-benzylhydroxylamine (0.612 ml, 5.32 mmol) over 5 minutes. Theresulting solution was stirred at -20° C. for one hour and then cooledto -40° C.

To the so-formed cold solution was added, via cannula over 10 minutes,the cold acid chloride solution formed in step H while -40° C. wasmaintained. Effluent acid chloride as it entered the coupling reactionvessel measured -33° C. and no exotherm in the reaction mixture wasnoticed. The nearly colorless reaction mixture was stirred at -40° C.for 45 minutes. Quench and workup was accomplished by pouring the coldreaction mixture into, and washing with, sodium phosphate buffer (pH2.0, 0.2M, 2×100 mL). Layer separation was quick and each aqueous layerwas back extracted with dichloromethane (10 mL). The combined cloudy,nearly colorless organic layers were dried over sodium sulfate,filtered, and reduced in vacuo to an oily solid. The compound wasdissolved in ethyl acetate (24 mL) and precipitated by the slow additionof diethyl ether (40 mL) into the rapidly stirred solution, followed bythe more rapid addition of ether (120 mL) to complete precipitation.Filtration, cake rinse (ether), and drying at ambient temperature underhigh vacuum produced 5.14 g of the slightly static-laden title Icompound as a finely divided white powder, m.p. 198°-220° C.

Analysis calc'd for C₄₅ H₅₀ N₁₀ O₁₆ S₂.0.42H₂ O. 0.05EtOAC.0.03 HCl: C,51.03; H, 4.86; N, 13.17; S, 6.03; Cl, 0.08; KF, 0.72;

Found: C, 50.93; H, 4.81; N, 13.07; S, 6.09; Cl, 0.08; KF 0.72.

J.2-[[[1-(2-Amino-4-thiazolyl)-2-[[1-[[[[3-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy-2-methylpropanoicacid, disodium salt

To trifluoroacetic acid (40 ml) at -2° C. under argon was added anisole(16 ml). To this solution was added the title I compound (10.0 g, 9.51mmol) over 5 minutes. The resulting mixture was stirred at -2° C. for 5hours. The reaction mixture was diluted with ethyl acetate (80 ml)followed by the addition of cyclohexane (160 ml). After stirring for 5minutes, the resulting suspension was filtered and the product cake waswashed with ethyl acetate/cyclohexane (1:2, 2×50 ml), ethylacetate/cyclohexane (1:1, 1×50 ml), and ethyl ether (2×25 ml). Afterdrying, the product was suspended in water and the pH was adjusted to6.0 by the addition of sodium bicarbonate. The resulting solution wasthen chromatographed on HP-20 to give the title compound afterlyophilization.

EXAMPLE 22-[[[1-(2-Amino-4-thiazolyl)-2-[[1-[[[[3-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy-2-methylpropanoicacid, disodium salt A. (S)-2-[[[1-(2-Amino-4-thiazolyl)-2-[[1-[[[[3-amino-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoicacid, diphenylmethyl ester

To a slurry of the title D compound from Example 1 (1.50 g, 1.99 mmol)in acetonitrile (30 mL) was added 0.2M sodium hydrogen phosphate (30 mL,pH 4.7). After 10 minutes at 35° C., the title D compound from Example 1dissolved and a vacuum was applied. During the next 65 minutes, solventwas slowly distilled with the aid of a 35° C. warming bath and thevolume of the reaction mixture was kept constant with the addition ofacetonitrile as required. The pH of the solution was lowered withphosphoric acid and the resulting solution was poured into methylenechloride (60 mL) and shaken. The organic layer was removed and theaqueous layer was extracted with methylene chloride:CH₃ CN (2:1, 15 mL).The combined organic layers were dried over anhydrous magnesium sulfate,filtered and concentrated to a white solid which was dried under highvacuum at ambient temperature to give 1.303 g of the title A compound,m.p. 160° C.

Analysis calc'd for C₂₉ H₃₁ N₉ O₉ S₂.1.0H₂ O.0.10CH₃ CN.0.015 TFA C,47.66; H, 4.56; N, 17.32; S, 8.71; F, 0.12; Na, 0; KF, 2.40;

Found: C, 47.92; H, 4.34; N, 16.97; S, 8.57; F, 0.12; Na, 0; KF, 2.31.

B.[3S(Z)]-2-[[[1-(2-Amino-4-thiazolyl)-2-[[1-[[[[3-[[[4,5-bis[[(1,1-dimethylethoxy)carbonyl]oxy]-2-pyridinyl]carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoicacid, diphenylmethyl ester

To a solution of the title A compound (1.30 g, 1.82 mmol) in drydichloromethane (30 ml) at -40° C. under argon was addeddiisopropylethylamine (0.33 ml, 1.91 mmol). To this solution, viacannula, was added the cold (-40° C.) acid chloride (˜1.91 mmol)solution of the title H compound from Example 1. After stirring for 45minutes at -40° C., the reaction was quenched and worked up by pouringthe cold reaction mixture into, and washing with, sodium phosphatebuffer (pH 2.0, 0.2M, 2×50 ml). Layer separation was rapid and eachaqueous layer was back extracted with dichloromethane (10 ml). Thecombined organic layers were dried over sodium sulfate, filtered, andreduced in vacuo to an oily solid. The compound was dissolved in ethylacetate (12 ml) and precipitated by the slow addition of diethyl ether(20 ml) into the rapidly stirred solution, followed by the more rapidaddition of ether (60 ml) to complete the precipitation. Filtration,cake rinse (ether) and drying at ambient temperature produced 1.67 g ofthe title B compound as a finely divided white powder, m.p. 198°-220° C.

C.2-[[[1-(2-Amino-4-thiazolyl)-2-[[1-[[[[3-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy-2-methylpropanoicacid, disodium salt

The procedure from Example 1, part J was used to convert the title Bcompound to the desired product.

What is claimed is:
 1. A process for making a compound of the formula##STR64## including pharmaceutically acceptable salts thereof,comprising the steps of(a) treating a compound of the formula ##STR65##in the presence of a ketonic solvent having the formula ##STR66## withhydrogen in the presence of a catalyst and thereafter, acylating toprovide a compound of the formula ##STR67## (b) removing the alkylideneor cycloalkylidene group from compound IV and coupling the so-preparedcompound with a compound having the formula ##STR68## wherein Prot is aphenol protecting group, (c) deprotecting the compound formed in step(b) to provide the compounds of formula I:wherein Z isbenzyloxycarbonyl; X is hydrogen, alkali earth metal or a tri-ortetra-alkylammonium group; R and R' are each alkyl or R and R' takentogether with the carbon atom to which they are attached are a 5-, 6- or7-membered cycloalkylidene group; wherein A₁ is --HN--, ##STR69## R₁ isan acyl group derived from a carboxylic acid; and, R₂ and R₃ are thesame or different and each is hydrogen, alkyl, cycloalkyl, phenyl,substituted phenyl or a 4, 5, 6 or 7-membered heterocycle (hereinafterreferred to as R_(x)), or one of R₂ and R₃ is hydrogen and the other ishalomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, carboxyl, --CH₂X₁ (wherein X₁ is amino, hydroxy, carboxyl, alkoxycarbonyl,alkanoylamino, phenylcarbonylamino, (substituted phenyl)carbonylamino,alkylsulfonyloxy, phenylsulfonyloxy, (substituted phenyl)sulfonyloxy,phenyl, substituted phenyl cyano, ##STR70## or --O--X₂ (wherein A₂, X₂,X₆ and X₇ are as hereinafter defined)), or --O--X₂ (wherein X₂ is alkyl,substituted alkyl, phenyl, substituted phenyl, phenylalkyl, (substitutedphenyl)alkyl, alkanoyl, phenylalkanoyl, (substituted phenyl)alkanoyl,phenylcarbonyl, (substituted phenyl)carbonyl, or heteroarylcarbonyl),##STR71## (wherein one of X₃ and X₄ is hydrogen and the other ishydrogen or alkyl, or X₃ and X₄ when taken together with the carbon atomto which they are attached form a cycloalkyl group; and X₅ is formyl,alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl,phenylalkylcarbonyl, (substituted phenyl)alkylcarbonyl, carboxyl,alkoxycarbonyl, aminocarbonyl, (substituted amino) carbonyl, or cyano),or ##STR72## (wherein A₂ is --(CH₂)_(m) --, --(CH₂)_(m) --O--, or--(CH₂)_(m) --NH--, m is 0, 1 or 2, and X₆ and X₇ are the same ordifferent and each is hydrogen, alkyl, phenyl or substituted phenyl, orX₆ is hydrogen and X₇ is amino, substituted amino, alkanoylamino oralkoxy, or X₆ and X₇ when taken together with the nitrogen atom to whichthey are attached form a 4, 5, 6 or 7-membered heterocycle); the terms"alkyl" and "alkoxy" refer to both straight and branched chain groupshaving 1 to 10 carbon atoms; the terms "cycloalkyl" and "cycloalkenyl"refer to cycloalkyl and cycloalkenyl groups having 3, 4, 5, 6 or 7carbon atoms; the term "substituted alkyl" refers to alkyl groupssubstituted with 1, 2 or 3 azido, amino, halogen, hydroxy, carboxy,cyano, alkoxycarbonyl, aminocarbonyl, alkanoyloxy, alkoxy, phenyloxy,(substituted phenyl)oxy, alkylsulfinyl, or alkylsulfonyl groups; theterms "alkanoyl", "alkenyl", and "alkynyl" refer to both straight andbranched chain groups having 2 to 10 carbon atoms; the terms "halogen"and "halo" refer to fluorine, chlorine, bromine and iodine; the term"substituted phenyl" refers to a phenyl group substituted with 1, 2 or 3amino, halogen, hydroxyl, trifluoromethyl, alkyl (of 1 to 4 carbonatoms), alkoxy (of 1 to 4 carbon atoms), alkanoyloxy, aminocarbonyl, orcarboxy groups; the expression "a 4, 5, 6 or 7-membered heterocycle"refers to substituted and unsubstituted, aromatic and non-aromaticheterocycle groups, wherein each may contain 1, 2 or 3 nitrogen oroxygen atoms and wherein substituents are selected from oxo, halogen,hydroxy, nitro, amino, cyano trifluoromethyl, alkyl of 1 to 4 carbons,alkoxy of 1 to 4 carbons, alkylsulfonyl, phenyl, substituted phenyl2-furfurylideneamino benzylideneamino and substituted alkyl groupswherein the alkyl group has 1 to 4 carbons, wherein said aromatic groupsare selected from pyridinyl, furanyl, pyrrolyl, 1,2,3-triazolyl,1,2,4-triazolyl, imidazolyl, pyrimidinyl, oxazolyl, triazinyl, andtetrazolyl; and said nonaromatic groups are selected from azetidinyl,oxetanyl, piperidinyl, piperazinyl, imidazolidinyl, oxazolidinyl,pyrrolidinyl, tetrahydropyrimidinyl and hexahydroazepinyl.
 2. A processof claim 1 wherein X is a tri-or tetra-alkylammonium group.
 3. A processof claim 2 wherein X is a tetrabutylammonium group.
 4. A process ofclaim 1 wherein said ketonic solvent is selected from acetone, diethylketone and methylethyl ketone.
 5. A process of claim 4 wherein saidketonic solvent is acetone.
 6. A process of claim 1 wherein R₁ is##STR73##
 7. A process of claim 1 wherein A₁ is ##STR74##
 8. A processof claim 1 wherein R₂ and R₃ are each hydrogen.
 9. A process of claim 1wherein the compound of formula I is ##STR75##
 10. A process of claim 1wherein the compounds of formula II are prepared bytreating a compoundof the formula

    H--A.sub.1 --H

with a nitrosating reagent, followed by reduction and reaction with acompound of the formula

    halogen--Z

followed by treatment with an acid to provide a compound of the formula

    H--A.sub.1 --NH--Z

which is reacted with a compound of the formula ##STR76## wherein Y is aleaving group, in the presence of a tertiary alkylamine and a solvent toprovide compounds of formula II wherein X is hydrogen or an alkalineearth metal; and, treating a so-formed compound with a tri- ortetra-alkylammonium sulfate to provide compounds of formula II wherein Xis a tri- or tetra-alkylammonium group.
 11. A process of claim 10wherein said nitrosating reagent is sodium nitrite in aqueous sulfuricacid.
 12. A process of claim 10 wherein said reduction is carried out bytreatment with zinc.
 13. A process of claim 10 wherein said acid ishydrochloric.
 14. A process of claim 10 wherein said tertiary alkylamineis selected from triethylamine and diisopropylethylamine.